Safety, Pharmacokinetics, and Efficacy Signals of Larsucosterol (DUR-928) in Alcohol-Associated Hepatitis.

INTRODUCTION: This study is to evaluate the safety and pharmacokinetics (PK) of larsucosterol (DUR-928 or 25HC3S) in subjects with alcohol-associated hepatitis (AH), a devastating acute illness without US Food and Drug Administration-approved therapies. METHODS: This phase 2a, multicenter, open-label, dose escalation study evaluated the safety, PK, and efficacy signals of larsucosterol in 19 clinically diagnosed subjects with AH. Based on the model for end-stage liver disease (MELD) score, 7 subjects were considered to have moderate AH and 12 to have severe AH. All subjects received 1 or 2 intravenous infusions (72 hours apart) of larsucosterol at a dose of 30, 90, or 150 mg and were followed up for 28 days. Efficacy signals from a subgroup of subjects with severe AH were compared with those from 2 matched arms of those with severe AH treated with standard of care (SOC), including corticosteroids, from a contemporaneous study. RESULTS: All 19 larsucosterol-treated subjects survived the 28-day study. Fourteen (74%) of all subjects including 8 (67%) of the subjects with severe AH were discharged ≤72 hours after receiving a single infusion. There were no drug-related serious adverse events nor early terminations due to the treatment. PK profiles were not affected by disease severity. Biochemical parameters improved in most subjects. Serum bilirubin levels declined notably from baseline to day 7 and day 28, and MELD scores were reduced at day 28. The efficacy signals compared favorably with those from 2 matched groups treated with SOC. Lille scores at day 7 were <0.45 in 16 of the 18 (89%) subjects with day 7 samples. Lille scores from 8 subjects with severe AH who received 30 or 90 mg larsucosterol (doses used in phase 2b trial) were statistically significantly lower ( P < 0.01) than those from subjects with severe AH treated with SOC from the contemporaneous study. DISCUSSION: Larsucosterol was well tolerated at all 3 doses in subjects with AH without safety concerns. Data from this pilot study showed promising efficacy signals in subjects with AH. Larsucosterol is being evaluated in a phase 2b multicenter, randomized, double-blinded, placebo-controlled (AHFIRM) trial.

Pulmonary tumour thrombotic microangiopathy mimicking immunotherapy-associated pneumonitis.

We present a case of pulmonary tumour thrombotic microangiopathy (PTTM) in a patient on adjuvant immunotherapy for resected triple negative breast cancer. The patient presented with deranged liver function tests and subsequently developed severe hypoxia and thrombocytopaenia, with right heart failure. The primary differential diagnosis considered was immunotherapy-associated hepatitis and pneumonitis. Despite organ support, the patient deteriorated rapidly and died of respiratory failure. As is often the case with PTTM, the diagnosis was only found at postmortem. PTTM should be considered in patients with a background of cancer (and may be more common in certain subtypes) who present with this unusual combination of clinical features. While the condition carries an extremely poor prognosis, prompter recognition for future patients may allow consideration of novel treatments.

The health of rural Black communities during COVID: Some affirmations, some surprises.

Background and objective: There are overwhelming health disparities in the Deep South. It is important to include the voice of communities affected by these disparities when developing interventions. The goal of the current study was to develop an academic community engaged partnership to strengthen the ability to address priority health concerns of rural African American communities with a focus on health literacy and health advocacy. Methods: A community-based participatory research approach was used to administer a 15-item community health survey in five rural communities led by African American mayors in Alabama (N = 752). The survey assessed the health concerns and the potential behaviors that may be associated with those health concerns. Results: The five communities demonstrated similarities as well as differences in both the health concerns endorsed and the potential health behaviors that may contribute to those concerns. All five communities identified cardiovascular disease as a health concern with three endorsing mental health issues and 2 dental health. With respect to behaviors, all five communities identified either unhealthy eating/exercise and substance use as concerns with one community identifying racism as a risky behavior affecting health. Conclusion: The results presented replicate CBPR studies demonstrating that communities are important sources of information about local health priorities and concerns.

A review of occupational safety and health research for American Indians and Alaska Natives.

INTRODUCTION: To better understand what is known about issues affecting American Indian and Alaska Native (AI/AN) workers, authors conducted a literature review of publications specific to AI/AN and occupational safety and health. METHODS: Search criteria included: (a) American Indian tribes and Alaska Native villages in the United States; (b) First Nations and aboriginals in Canada; and (c) occupational safety and health. RESULTS: Results of two identical searches in 2017 and 2019 identified 119 articles and 26 articles respectively, with references to AI/AN people and occupation. Of the 145 total articles, only 11 articles met the search criteria for addressing occupational safety and health research among AI/AN workers. Information from each article was abstracted and categorized according to National Occupational Research Agenda (NORA) sector, resulting in: four articles related to agriculture, forestry, and fishing; three related to mining; one related to manufacturing; and one related to services. Two articles reported on AI/AN people and occupational well-being in general. CONCLUSIONS: The review was limited by the small number and age of relevant articles, reflecting the likelihood that findings could be out of date. General themes across the reviewed articles point to the need for increased overall awareness and education regarding injury prevention and risks associated with occupational injuries and fatalities among AI/AN workers. Similarly, increased use of personal protective equipment (PPE) is recommended for the agriculture, forestry, and fishing industries, as well as for workers exposed to metals dust. PRACTICAL APPLICATIONS: The lack of research in most NORA sectors indicates the need for heightened research efforts directed toward AI/AN workers.

The Incidence and Temporal Patterns of Use of Amphetamine-Type Stimulant Use in Traffic-Related Ambulance Attendances From 2015 to 2020 in Victoria, Australia.

OBJECTIVE: Amphetamine-type stimulants are increasingly implicated in road trauma incidents. Although ambulances are typically first to attend these emergencies, limited research has used paramedic clinical data to examine the contribution of amphetamine use to road trauma-related ambulance attendances. We describe the clinical and temporal risk profiles associated with amphetamine-related harm in road trauma incidents requiring paramedic attendance in the Australian state of Victoria. METHOD: This cross-sectional, retrospective observational study examined the Victorian component of a national surveillance data set (National Ambulance Surveillance System) of alcohol and other drug (AOD)-related ambulance attendances to determine the incidence and temporal profile of amphetamine use in traffic-related ambulance attendances from January 2015 to December 2020. RESULTS: Throughout the observation period, Victorian paramedics attended 8,163 alcohol, pharmaceutical, or illicit drug-related cases involving a road trauma. More than one quarter (2,161 cases, 27.4%) of these attendances were deemed related to the use of pharmaceutical and/or illicit drugs. Amphetamine alone was involved in nearly one third (640 cases, 29.6%) of non-alcohol-related road trauma attendances, and co-consumption of amphetamine with drugs other than alcohol occurred in more than one third (35.3%) of all AOD-related traffic incidents. Amphetamine-related road trauma attendances predominantly occurred on the weekend (Fri-Sun) during late night/early morning in metropolitan Melbourne. Between 2015 and 2020, the incidence of amphetamine-related road trauma ambulance attendances increased by 86.8%, from 1.1 per 100,000 population in 2015 to 1.9 per 100,000 population in 2020. CONCLUSIONS: Amphetamine-type stimulants are increasingly implicated in road trauma. Co-consumption with other potentially impairing substances reflects a concerning trend of polysubstance use among Victorian drivers.

Hairstyling Practices to Prevent Hair Damage and Alopecia in Women of African Descent.

Highly textured hair has been found to be more susceptible to breakage than other hair types due to an increased proportion of spirals and relatively fewer elastic fibers anchoring the hair follicles to the dermis. Women of African descent frequently employ hairstyles and hair treatments for ease of management and as a form of self-expression, but a number of these practices have been implicated as risk factors for alopecia. Herein, we provide an overview of hairstyles for patients with highly textured hair so that physicians may better identify high-risk hairstyles, provide individualized recommendations for safer alternatives, and manage and stop the progression of hair loss before it becomes permanent.

Services and Challenges at a Native American Residential Substance Use Disorder Treatment Center during the COVID-19 Pandemic.

During the COVID-19 pandemic, challenges arose for a Native American residential substance use disorder treatment program in California (e.g., insufficient housing for quarantining, inadequate telehealth bandwidth, food shortages, client skepticism regarding safety needs). These challenges were addressed, culturally appropriate services continued, no clients tested positive for COVID-19, and unexpected benefits arose.

Identifying Points of Prevention in Firearm-Related Suicides: A Mixed-Methods Study Based on Coronial Records.

PURPOSE: Firearm-related suicide is a noteworthy and preventable public health issue that has drawn limited attention in Australian research. Firearms are highly lethal and remain in the top three methods of suicide among Australian males. This study examines suicides occurring in Tasmania, the jurisdiction with the highest rate of firearm-related suicide, with the aim of aiding suicide prevention strategies. METHODS: A mixed-methods approach was used to analyze data from the Tasmanian Suicide Register. The quantitative analysis examined socio-demographic factors, substance use, physical and mental health, and access to services for suicides occurring between January 1, 2012 and December 31, 2016. The qualitative analysis comprised firearm-related suicides occurring between January 1, 2012 and December 31, 2017. RESULTS: Firearms users were more likely than those employing other means of suicide to be male, retired, and residing in remote areas but were less likely to have had a previous mental illness diagnosis or evidence of suicidal ideation or self-harming behaviors. There was some evidence of increased impulsiveness among firearm users. We found 54% of decedents were licensed to own a firearm at the time of death. Firearms most often belonged to the decedent (52%) and 26% sourced a firearm from family or friends. Only 58% of cases involved a firearm with a dedicated storage facility. CONCLUSIONS: Prevention efforts need to take into account the unique profiles of those at risk of firearm-related suicide. Impulsiveness and the varying levels of adherence to firearms safety practices point to the need for strategies that limit physical access to firearms.HIGHLIGHTSFirearms-related suicides have a unique risk profile compared with other means of suicide.Mental illness diagnosis, suicidal thoughts, and self-harming behaviors were less commonly identified among firearms-related suicides than other means of suicide.Impulsiveness and the varying levels of adherence to firearms safety practices point to the need for strategies that limit physical access to firearms.

Brigham Eyebrow Tool for Alopecia: A Reliable Assessment of Eyebrow Alopecia Areata.

There are no tools to evaluate eyebrow involvement in patients with alopecia areata. We developed and assessed the reliability of the Brigham Eyebrow Tool for Alopecia (BETA) as a quantitative evaluation of eyebrow alopecia areata. BETA uses facial landmarks of eyebrow anatomy and is calculated using surface area and density. A total of 50 eyebrow images with varying levels of hair loss were distributed to six board-certified dermatologists at three academic medical centers with standardized instructions and examples. Interrater and intrarater reliability were calculated using intraclass correlation coefficients (ICCs). BETA demonstrated high interrater (ICC = 0.88, confidence interval = 0.83-0.92 right eyebrow scores and ICC = 0.90, confidence interval = 0.85-0.94 left eyebrow scores) and intrarater (ICC = 0.90, confidence interval = 0.85-0.93 right eyebrow scores and ICC = 0.91, confidence interval = 0.87-0.94 left eyebrow scores) reliability. When measured in the same patient with varying degrees of hair loss over time, BETA demonstrated sensitivity to change. BETA is a simple and reliable objective assessment of eyebrow alopecia areata. BETA is easy-to-use and quick to calculate, making it feasible for a variety of clinical and research settings. Although developed for alopecia areata, we hope that BETA will be investigated in other etiologies of eyebrow alopecia to serve as a universal tool for monitoring disease progression, improvement, and response to treatment.

Digital biopiracy and the (dis)assembling of the Nagoya Protocol.

Technological leaps in DNA sequencing and synthesis are disrupting tenuous access and benefit-sharing (ABS) arrangements between 'users' and 'providers' of genetic resources. For some this signals a new era of open-source gene banks to address global challenges, but to others it threatens a new wave of unjust digital biopiracy. This paper explores the issue of digital sequence information (DSI) at the 2016 Cancun negotiations of the UN Convention on Biological Diversity and its Nagoya Protocol on ABS, and its continued relevance today. While some research has addressed potential solutions to digital sequencing and ABS, little attention has been paid to the problematization of the issue itself. This paper addresses this gap with a fine-grained view of the negotiations as an ethnographic site of contestation. We approach the Nagoya Protocol as an assemblage seeking to govern ABS. We trace how the unruly component of DSI threatens this already fragile assemblage by disrupting simplified notions of genetic resources, scientific discovery, and R&D. Our data from the negotiations reveals three major points of tension: the materiality of genetic resources; the problem's novelty; and the problem's urgency. Two opposing solutions raised in response to these contestations reveal underlying faultlines that we argue will continue to destabilise the broader ABS assemblage if left unresolved. Our attention to processes of assemblage (trans)formation offers insights to the historically fragile arrangements of ABS and, more broadly, assemblages of global environmental governance in the context of rapid technological change.

Bioengineering horizon scan 2020.

Horizon scanning is intended to identify the opportunities and threats associated with technological, regulatory and social change. In 2017 some of the present authors conducted a horizon scan for bioengineering (Wintle et al., 2017). Here we report the results of a new horizon scan that is based on inputs from a larger and more international group of 38 participants. The final list of 20 issues includes topics spanning from the political (the regulation of genomic data, increased philanthropic funding and malicious uses of neurochemicals) to the environmental (crops for changing climates and agricultural gene drives). The early identification of such issues is relevant to researchers, policy-makers and the wider public.

Self-reported sleep disturbance in ambulance attendances for suicidal ideation and attempted suicide between 2012 and 2017.

BACKGROUND: Sleep disturbances are among the top-ten warning signs for suicide, however there has been limited investigation of the relationship between these variables in acute presentations, particularly community settings. We examined ambulance attendances for suicide ideation and attempt to explore the role of sleep and co-morbid factors (mental health symptoms, attendance time, and alcohol and benzodiazepine use). METHODS: Coded clinical records from Ambulance Victoria for the period 1 January 2012 to 30 June 2017 were analysed. RESULTS: Paramedics attended 97,198 cases of suicidal ideation or suicide attempt during the study period. Just over half (56.4%) of these were for suicidal ideation, and 43.6% were for attempted suicide. Depression symptomology-related attendances were more common than those for anxiety and despite a lower proportion of both sleep and current anxiety-related symptoms, benzodiazepine use was significantly more common in attendances for suicide attempts (25.9%) than for ideation (2.2%). Co-morbid benzodiazepine use was associated with attempted suicide (OR: 10.37 (10.04-10.72), in a hierarchical regression model. LIMITATIONS: Data represent self-report/paramedic observation only, and do include validated measures of sleep or drug use. Sleep disturbance is likely under recorded in ambulance attendances given the primary role of paramedics is to stabilise patients, and minimise risk of harm during transport. CONCLUSION: This study reports internationally unique data, and provides the first examination of ambulance coded clinical records for suicide ideation and attempt. Sleep disturbances had a unique role in these attendances, over and above common co-occurring factors including drug use and mental health diagnoses.

Unusual subunits are directly involved in binding substrates for natural rubber biosynthesis in multiple plant species.

Rubber particles from rubber-producing plant species have many different species-specific proteins bound to their external monolayer biomembranes. To date, identification of those proteins directly involved in enzymatic catalysis of rubber polymerization has not been fully accomplished using solubilization, purification or reconstitution approaches. In an alternative approach, we use several tritiated photoaffinity-labeled benzophenone analogs of the allylic pyrophosphate substrates, required by rubber transferase (RT-ase) to initiate the synthesis of new rubber molecules, to identify the proteins involved in catalysis. Enzymatically-active rubber particles were purified from three phylogenetically-distant rubber producing species, Parthenium argentatum Gray, Hevea brasiliensis Muell. Arg, and Ficus elastica Roxb., each representing a different Superorder of the Dicotyledonae. Geranyl pyrophosphate with the benzophenone in the para position (Bz-GPP(p)) was the most active initiator of rubber biosynthesis in all three species. When rubber particles were exposed to ultra-violet radiation, 95% of RT-ase activity was eliminated in the presence of 50 µΜ Bz-GPP(p), compared to only 50% of activity in the absence of this analog. 3H-Bz-GPP(p) then was used to label and identify the proteins involved in substrate binding and these proteins were characterized electrophoretically. In all three species, three distinct proteins were labeled, one very large protein and two very small proteins, as follows: P. argentatum 287,000, 3,990, and 1,790 Da; H. brasiliensis 241,000, 3,650 and 1,600 Da; F. elastica 360,000, 3,900 and 1,800 Da. The isoelectric points of the P. argentatum proteins were 7.6 for the 287,000 Da, 10.4 for the 3,990 Da and 3.5 for the 1,790 Da proteins, and of the F. elastica proteins were 7.7 for the 360,000 Da, 6,0 for the 3,900 Da, and 11.0 for the 1,800 Da proteins. H. brasiliensis protein pI values were not determined. Additional analysis indicated that the three proteins are components of a membrane-bound complex and that the ratio of each small protein to the large one is 3:1, and the large protein exists as a dimer. Also, the large proteins are membrane bound whereas both small proteins are strongly associated with the large proteins, rather than to the rubber particle proteolipid membrane.

Development and pilot-testing of the Alopecia Areata Assessment Tool (ALTO).

BACKGROUND: Alopecia areata (AA) is an autoimmune disease characterized by non-scarring hair loss. The lack of a definitive biomarker or formal diagnostic criteria for AA limits our ability to define the epidemiology of the disease. In this study, we developed and tested the Alopecia Areata Assessment Tool (ALTO) in an academic medical center to validate the ability of this questionnaire in identifying AA cases. METHODS: The ALTO is a novel, self-administered questionnaire consisting of 8 closed-ended questions derived by the Delphi method. This prospective pilot study was administered during a 1-year period in outpatient dermatology clinics. Eligible patients (18 years or older with chief concern of hair loss) were recruited consecutively. No patients declined to participate. The patient's hair loss diagnosis was determined by a board-certified dermatologist. Nine scoring algorithms were created and used to evaluate the accuracy of the ALTO in identifying AA. RESULTS: 239 patients (59 AA cases and 180 non-AA cases) completed the ALTO and were included for analysis. Algorithm 5 demonstrated the highest sensitivity (89.8%) while algorithm 3 demonstrated the highest specificity (97.8%). Select questions were also effective in clarifying disease phenotype. CONCLUSION: In this study. we have successfully demonstrated that ALTO is a simple tool capable of discriminating AA from other types of hair loss. The ALTO may be useful to identify individuals with AA within large populations.

An Update on Ocular Surface Epithelial Stem Cells: Cornea and Conjunctiva.

The human ocular surface (front surface of the eye) is formed by two different types of epithelia: the corneal epithelium centrally and the conjunctival epithelium that surrounds this. These two epithelia are maintained by different stem cell populations (limbal stem cells for the corneal epithelium and the conjunctival epithelial stem cells). In this review, we provide an update on our understanding of these epithelia and their stem cells systems, including embryology, new markers, and controversy around the location of these stem cells. We also provide an update on the translation of this understanding into clinical applications for the treatment of debilitating ocular surface diseases.

Altered levels of the Taraxacum kok-saghyz (Russian dandelion) small rubber particle protein, TkSRPP3, result in qualitative and quantitative changes in rubber metabolism.

Several proteins have been identified and implicated in natural rubber biosynthesis, one of which, the small rubber particle protein (SRPP), was originally identified in Hevea brasiliensis as an abundant protein associated with cytosolic vesicles known as rubber particles. While previous in vitro studies suggest that SRPP plays a role in rubber biosynthesis, in vivo evidence is lacking to support this hypothesis. To address this issue, a transgene approach was taken in Taraxacum kok-saghyz (Russian dandelion or Tk) to determine if altered SRPP levels would influence rubber biosynthesis. Three dandelion SRPPs were found to be highly abundant on dandelion rubber particles. The most abundant particle associated SRPP, TkSRPP3, showed temporal and spatial patterns of expression consistent with patterns of natural rubber accumulation in dandelion. To confirm its role in rubber biosynthesis, TkSRPP3 expression was altered in Russian dandelion using over-expression and RNAi methods. While TkSRPP3 over-expressing lines had slightly higher levels of rubber in their roots, relative to the control, TkSRPP3 RNAi lines showed significant decreases in root rubber content and produced dramatically lower molecular weight rubber than the control line. Not only do results here provide in vivo evidence of TkSRPP proteins affecting the amount of rubber in dandelion root, but they also suggest a function in regulating the molecular weight of the cis-1, 4-polyisoprene polymer.

BeLieving in Native Girls: characteristics from a baseline assessment.

BeLieving In Native Girls (BLING) is a juvenile delinquency and HIV intervention at a residential boarding school for American Indian/Alaska Native adolescent girls ages 12-20 years. In 2010, 115 participants completed baseline surveys to identify risk and protective factors. Initial findings are discussed regarding a variety of topics, including demographics and general characteristics, academic engagement, home neighborhood characteristics and safety, experience with and perceptions of gang involvement, problem-solving skills, self-esteem, depression, sexual experiences and risk-taking behaviors, substance abuse, and dating violence.